Striated muscle activator of Rho signalling (STARS) is a PGC-1α/oestrogen-related receptor-α target gene and is upregulated in human skeletal muscle after endurance exercise

Non-technical summary Exercise improves the ability of skeletal muscle to metabolise fats and sugars. For these improvements to occur the muscle detects a signal caused by exercise, resulting in changes in genes and proteins that control metabolism. We show that endurance exercise increases the amount of a protein called striated muscle activator of Rho signalling (STARS) as well as several other proteins influenced by STARS. We also show that the amount of STARS can be increased by signals directed from proteins called peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1 alpha) and oestrogen-related receptor-alpha (ERR alpha). We also observed that when we reduce the amount of STARS in muscle cells, we block the ability of PGC-1 alpha/ERR alpha to increase a gene called carnitine palmitoyltransferase-1 beta (CPT-1 beta), which is important for fat metabolism. Our study has shown that the STARS pathway is regulated by endurance exercise. STARS may also play a role in fat metabolism in muscle.The striated muscle activator of Rho signalling (STARS) is an actin-binding protein specifically expressed in cardiac, skeletal and smooth muscle. STARS has been suggested to provide an important link between the transduction of external stress signals to intracellular signalling pathways controlling genes involved in the maintenance of muscle function. The aims of this study were firstly, to establish if STARS, as well as members of its downstream signalling pathway, are upregulated following acute endurance cycling exercise; and secondly, to determine if STARS is a transcriptional target of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1 alpha) and oestrogen-related receptor-alpha (ERR alpha). When measured 3 h post-exercise, STARS mRNA and protein levels as well as MRTF-A and serum response factor (SRF) nuclear protein content, were significantly increased by 140, 40, 40 and 40%, respectively. Known SRF target genes, carnitine palmitoyltransferase-1 beta (CPT-1 beta) and jun B proto-oncogene (JUNB), as well as the exercise-responsive genes PGC-1 alpha mRNA and ERR alpha were increased by 2.3-, 1.8-, 4.5- and 2.7-fold, 3 h post-exercise. Infection of C2C12 myotubes with an adenovirus-expressing human PGC-1 alpha resulted in a 3-fold increase in Stars mRNA, a response that was abolished following the suppression of endogenous ERR alpha. Over-expression of PGC-1 alpha also increased Cpt-1 beta, Cox4 and Vegf mRNA by 6.2-, 2.0- and 2.0-fold, respectively. Suppression of endogenous STARS reduced basal Cpt-1 beta levels by 8.2-fold and inhibited the PGC-1 alpha-induced increase in Cpt-1 beta mRNA. Our results show for the first time that the STARS signalling pathway is upregulated in response to acute endurance exercise. Additionally, we show in C2C12 myotubes that the STARS gene is a PGC-1 alpha/ERR alpha transcriptional target. Furthermore, our results suggest a novel role of STARS in the co-ordination of PGC-1 alpha-induced upregulation of the fat oxidative gene, CPT-1 beta.